Candidate: Lyndon Joseph, Ph.D., recently joined the faculty as an Assistant Professor in the Division of Gerontology, School of Medicine at the University of Maryland, Baltimore, making this an ideal time to request an MRSDA that will provide the protected research time to learn the molecular techniques necessary to broaden his understanding of whole body insulin action and to determine the cellular mechanism by which weight loss (WL) and aerobic exercise (AEX) improves glucose metabolism in high risk individuals. This will be accomplished via laboratory [unreadable] training, didactic course, and 1:1 mentoring. This training will extend Dr. Joseph's previous education and provide the advanced research skills necessary to launch an independent career in aging research. The long-term career goal of the candidate is to advance academically in a research institution conducting mechanistic research in the study of the pathogenesis of type 2 diabetes with aging and the molecular/cellular effects of exercise and dietary intervention on muscle and glucose metabolism. Background: Aging is associated with an increase in insulin resistance that may be affected more by obesity and physical inactivity than age per se. Insulin resistance is an underlying abnormality in [unreadable] various metabolic disorders such as type 2 diabetes, hyperlipidemia, and hypertension; metabolic diseases that increase cardiovascular morbidity and mortality with aging. Numerous studies show that moderate WL plus AEX improve glucose tolerance and insulin sensitivity in older individuals. However, the molecular and cellular mechanisms underlying these metabolic changes with WL+AEX are not certain. Hypothesis: It is our hypothesis that a lifestyle intervention that incorporates a moderate rate of WL (250-350 kcal/day deficit) plus AEX (70-75% heart rate reserve) will improve glucose tolerance and glucose utilization (80 mU/m2/min hyperinsulinemic-euglycemic clamp) in overweight (25-35 kg/m 2 body mass index), older (60-75 y) glucose intolerant men and women through cellular mechanisms that involve increases in the content, phosphorylation, or activity of intermediates of the insulin-signaling [unreadable] cascade in skeletal muscle (basal and insulin-stimulated muscle biopsies). The specific aim is to determine in-vivo the basal (Glut-4, IRS-1, PI 3-kinase, Akt-kinase protein levels) and insulin stimulated (IR, IRS-1, and CbltCAP phosphorylation, protein kinase C's, PI 3-kinase and AKT-kinase activity) cellular mechanisms in skeletal muscle that may contribute to improvement in glucose utilization after a 6-month WL+AEX program. Environment: The Divisions of Gerontology and Endocrinology, Diabetes and Nutrition at University of Maryland and Department of Physiology, East Carolina University have the resources necessary for my advanced research training in aging, exercise, nutrition, and metabolism research. My mentors, Dr. Goldberg (an investigator in exercise, nutrition and glucose metabolism in aging), and Dr. Dohm (an investigator in cellular and molecular biology of diabetes and obesity) compliment each other in providing me with training to study both whole body and cellular mechanisms of insulin resistance. [unreadable] [unreadable]